We propose to create an animal model of cerebral amyloid angiopathy (CAA), a growing and untreatable cause of stroke. Towards this end, we have developed lines of transgenic mice carrying multiple copies of the amyloid precursor protein (APP) gene with or without the APP Dutch mutation linked to the promoter for vascular smooth muscle actin. Preliminary data from these mice demonstrate strong expression of human APP. In the upcoming year, we propose to breed APP homozygotes from the highest expressing lines. We will also cross these animals with transgenic mice expressing the human apolipoprotein E (APOE) alleles shown to associate with CAA: APOE epsilon2 and epsilon4. The mice generated from these breeding strategies will be examined for evidence of amyloid deposition and the vasculopathic changes characteristic of CAA. Following qualitative and quantitative techniques developed in our laboratory in collaboration with Bradley Hyman, we will examine 1) the distributions of the 40 and 42 amino acid forms of the beta- amyloid peptide, 2) the proportion of vessels affected by each, and 3) the amount of amyloid per affected vessel. These values will be compared across multiple time points in individual lines for changes with disease progression as well as among different lines to determine the effect of APOE genotype. In future studies, we plan to use in situ techniques pioneered by our collaborator Michael Moskowitz to determine the effect of amyloid formation and deposition on cerebrovascular reactivity to physiologic stimuli. The steps outlined in this proposal comprise the groundwork for an open-ended investigation of the pathophysiology and ultimately the treatment of CAA. We envision a range of future uses for a reliable and well-characterized model of CAA, which will represent a strong resource for future investigations and collaborations.